Preadipocyte Factor-1 Levels Are Higher in Women with Hypothalamic Amenorrhea and Are Associated with Bone Mineral Content and Bone Mineral Density through a Mechanism Independent of Leptin

• Published in: The journal of clinical endocrinology and metabolism Vol. 96; no. 10; pp. E1634 - E1639
• Main Authors: Aronis, Konstantinos N, Kilim, Holly, Chamberland, John P, Breggia, Anne, Rosen, Clifford, Mantzoros, Christos S
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-10-2011; Copyright by The Endocrine Society
• Subjects: Adult; Amenorrhea; Amenorrhea - blood; Amenorrhea - drug therapy; Anorexia nervosa; Body Composition - physiology; Body Mass Index; Body Weight - physiology; Bone Density - drug effects; Bone Density - physiology; Bone mineral content; Bone mineral density; Clinical trials; Cross-Sectional Studies; Dose-Response Relationship, Drug; Double-Blind Method; Eating disorders; Energy Metabolism - physiology; Estradiol - blood; Exercise - physiology; Fasting; Female; Humans; Hypothalamic Diseases - blood; Hypothalamic Diseases - drug therapy; Hypothalamus; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-Like Growth Factor I - metabolism; Intercellular Signaling Peptides and Proteins - blood; JCEM Online: Brief Reports; Leptin; Leptin - analogs & derivatives; Leptin - deficiency; Leptin - pharmacology; Leptin - physiology; Leptin - therapeutic use; Membrane Proteins - blood; Preadipocyte factor 1; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2011-0600

Context:
Preadipocyte factor 1 (pref-1) is increased in anorexia nervosa and is associated negatively with bone mineral density (BMD). No previous studies exist on pref-1 in women with exercise-induced hypothalamic amenorrhea (HA), which similar to anorexia nervosa, is an energy-deficiency state associated with hypoleptinemia.
Objective:
Our objective was to evaluate whether pref-1 levels are also elevated and associated with low BMD and to assess whether leptin regulates pref-1 levels in women with HA.
Design:
Study 1 was a double-blinded, placebo-controlled randomized clinical trial of metreleptin administration in women with HA. Study 2 was an open-label study of metreleptin administration in low physiological, supraphysiological, and pharmacological doses in healthy women volunteers.
Setting and Patients:
At Beth Israel Deaconess Medical Center, 20 women with HA and leptin levels higher than 5 ng/ml and nine healthy control women participated in study 1, and five healthy women participated in study 2.
Intervention:
For study 1, 20 HA subjects were randomized to receive either 0.08 mg/kg metreleptin (n = 11) or placebo (n = 9). For study 2, five healthy subjects received 0.01, 0.1, and 0.3 mg/kg metreleptin in both fed and fasting conditions for 1 and 3 d, respectively.
Main Outcome Measures:
Circulating pref-1 and leptin levels were measured.
Results:
Pref-1 was significantly higher in HA subjects vs. controls (P = 0.035) and negatively associated with BMD (ρ = −0.38; P < 0.01) and bone mineral content (ρ = −0.32; P < 0.05). Metreleptin administration did not alter pref-1 levels in any study reported herein.
Conclusions:
Pref-1 is higher in HA subjects than controls. Metreleptin administration at low physiological, supraphysiological, and pharmacological doses does not affect pref-1 levels, suggesting that hypoleptinemia is not responsible for higher pref-1 levels and that leptin does not regulate pref-1.